Cyclopentane heptan(ene) acyl sulfonamide, 2-alkyl or 2-arylalkyl, or 2-heteroarylalkenyl derivatives as therapeutic agents

ABSTRACT

The present invention provides a method of treating ocular hypertension or glaucoma which comprises administering to an animal having ocular hypertension or glaucoma therapeutically effective amount of a compound represented by the general formula I;  
                 
 
     wherein a hatched line represents the α configuration, a triangle represents the β configuration, a straight line, e.g. at the 9, 11 or 15 position represents either the α or β configuration, a dotted line represents the presence or absence of a double bond; a wavy line represents a cis or trans bond;  
     X is 0, S, NH or (CH 2 ) n ;  
     n is 0 or an integer of from 1 to 4;  
     Y is C 1 -C 5  n-alkyl, C 3 -C 7  cycloalkyl, phenyl, furanyl, thienyl, pyridinyl, thiazolyl, benzothienyl, benzofuranyl, naphthyl, or substituted derivatives thereof, wherein the substituents maybe selected from the group consisting of C 1 -C 5  alkyl, halogen, CF 3 , CN, NO 2 , N(R 2 ) 2 , CO 2 R 2  and OR 2 ;  
     Z is (CH 2 ) n  or a covalent bond;  
     R is C 1 -C 6  lower alkyl or Z-CF 3  or mesylate or triflate;  
     R 1  is H, R 2  or COR 2 ;and  
     R 2  is H or C 1 -C 5  lower alkyl or 9, 11 or 15 esters thereof.

CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This patent application is a continuation of U.S. patentapplication Ser. No. 09/880,272, filed Jun. 13, 2001.

BACKGROUND OF THE INVENTION

[0002] 1. Field of the Invention

[0003] The present invention relates to cyclopentane heptan(ene) acylsulfonamide, 2-alkyl or 2-arylalkyl, or 2-heteroarylalkenyl derivativesas therapeutic agents, e.g. such agents are potent ocular hypotensivesthat are particularly suited for the management of glaucoma.

[0004] 2. Description of Related Art

[0005] Ocular hypotensive agents are useful in the treatment of a numberof various ocular hypertensive conditions, such as post-surgical andpost-laser trabeculectomy ocular hypertensive episodes, glaucoma, and aspresurgical adjuncts.

[0006] Glaucoma is a disease of the eye characterized by increasedintraocular pressure. On the basis of its etiology, glaucoma has beenclassified as primary or secondary. For example, primary glaucoma inadults (congenital glaucoma) may be either open-angle or acute orchronic angle-closure. Secondary glaucoma results from pre-existingocular diseases such as uveitis, intraocular tumor or an enlargedcataract.

[0007] The underlying causes of primary glaucoma are not yet known. Theincreased intraocular tension is due to the obstruction of aqueous humoroutflow. In chronic open-angle glaucoma, the anterior chamber and itsanatomic structures appear normal, but drainage of the aqueous humor isimpeded. In acute or chronic angle-closure glaucoma, the anteriorchamber is shallow, the filtration angle is narrowed, and the iris mayobstruct the trabecular meshwork at the entrance of the canal ofSchlemm. Dilation of the pupil may push the root of the iris forwardagainst the angle, and may produce pupilary block and thus precipitatean acute attack. Eyes with narrow anterior chamber angles arepredisposed to acute angle-closure glaucoma attacks of various degreesof severity.

[0008] Secondary glaucoma is caused by any interference with the flow ofaqueous humor from the posterior chamber into the anterior chamber andsubsequently, into the canal of Schlemm. Inflammatory disease of theanterior segment may prevent aqueous escape by causing completeposterior synechia in iris bombe, and may plug the drainage channel withexudates. Other common causes are intraocular tumors, enlargedcataracts, central retinal vein occlusion, trauma to the eye, operativeprocedures and intraocular hemorrhage.

[0009] Considering all types together, glaucoma occurs in about 2% ofall persons over the age of 40 and may be asymptotic for years beforeprogressing to rapid loss of vision. In cases where surgery is notindicated, topical b-adrenoreceptor antagonists have traditionally beenthe drugs of choice for treating glaucoma.

[0010] Certain eicosanoids and their derivatives have been reported topossess ocular hypotensive activity, and have been recommended for usein glaucoma management. Eicosanoids and derivatives include numerousbiologically important compounds such as prostaglandins and theirderivatives. Prostaglandins can be described as derivatives ofprostanoic acid which have the following structural formula:

[0011] Various types of prostaglandins are known, depending on thestructure and substituents carried on the alicyclic ring of theprostanoic acid skeleton. Further classification is based on the numberof unsaturated bonds in the side chain indicated by numerical subscriptsafter the generic type of prostaglandin [e.g. prostaglandin E₁ (PGE₁),prostaglandin E₂ (PGE₂)], and on the configuration of the substituentson the alicyclic ring indicated by α or β [e.g. prostaglandin F_(2α)(PGF_(2β))].

[0012] Prostaglandins were earlier regarded as potent ocularhypertensives, however, evidence accumulated in the last decade showsthat some prostaglandins are highly effective ocular hypotensive agents,and are ideally suited for the long-term medical management of glaucoma(see, for example, Bito, L. Z. Biological Protection withProstaglandins, Cohen, M. M., ed., Boca Raton, Fla., CRC Press Inc.,1985, pp. 231-252; and Bito, L. Z., Applied Pharmacology in the MedicalTreatment of Glaucomas Drance, S. M. and Neufeld, A. H. eds., New York,Grune & Stratton, 1984, pp. 477-505. Such prostaglandins includePGF_(2α), PGF₁, PGE₂, and certain lipid-soluble esters, such as C₁ to C₂alkyl esters, e.g. 1-isopropyl ester, of such compounds.

[0013] Although the precise mechanism is not yet known experimentalresults indicate that the prostaglandin-induced reduction in intraocularpressure results from increased uveoscleral outflow [Nilsson et.al.,Invest. Ophthalmol. Vis. Sci. (suppl), 284 (1987)].

[0014] The isopropyl ester of PGF_(2α) has been shown to havesignificantly greater hypotensive potency than the parent compound,presumably as a result of its more effective penetration through thecornea. In 1987, this compound was described as “the most potent ocularhypotensive agent ever reported” [see, for example, Bito, L. Z., Arch.Ophthalmol. 105, 1036 (1987), and Siebold et.al., Prodrug 5 3 (1989)].

[0015] Whereas prostaglandins appear to be devoid of significantintraocular side effects, ocular surface (conjunctival) hyperemia andforeign-body sensation have been consistently associated with thetopical ocular use of such compounds, in particular PGF_(2α) and itsprodrugs, e.g., its 1-isopropyl ester, in humans. The clinicalpotentials of prostaglandins in the management of conditions associatedwith increased ocular pressure, e.g. glaucoma are greatly limited bythese side effects.

[0016] In a series of co-pending United States patent applicationsassigned to Allergan, Inc. prostaglandin esters with increased ocularhypotensive activity accompanied with no or substantially reducedside-effects are disclosed. The co-pending U.S. Ser. No. 596,430 (filedOct. 10, 1990), relates to certain 11-acyl-prostaglandins, such as11-pivaloyl, 11-acetyl, 11-isobutyryl, 11-valeryl, and 11-isovalerylPGF_(2α). Intraocular pressure reducing 15-acyl prostaglandins aredisclosed in the co-pending application U.S. Ser. No. 175,476 (filedDec. 29, 1993). Similarly, 11,15-9,15 and 9,11-diesters ofprostaglandins, for example 11,15-dipivaloyl PGF_(2α) are known to haveocular hypotensive activity. See the co-pending patent applications U.S.Ser. Nos. 385,645 (filed Jul. 7, 1989, now U.S. Pat. No. 4,994,274),Ser. No. 584,370 (filed Sep. 18, 1990, now U.S. Pat. No. 5,028,624) andSer. No. 585,284 (filed Sep. 18, 1990, now U.S. Pat. No. 5,034,413). Thedisclosures of all of these patent applications are hereby expresslyincorporated by reference.

SUMMARY OF THE INVENTION

[0017] The present invention concerns a method of treating ocularhypertension which comprises administering to a mammal having ocularhypertension a therapeutically effective amount of a compound of formulaI

[0018] wherein a hatched line represents the α configuration, a trianglerepresents the β configuration, a straight line, e.g. at the 9, 11 or 15position, represents either the α or β configuration, a dotted linerepresents the presence or absence of a double bond; a wavy linerepresents a cis or trans bond;

[0019] X is O, S, NH or (CH₂)_(n);

[0020] n is 0 or an integer of from 1 to 4;

[0021] Y is C₁-C₅ n-alkyl, C₃-C₇ cycloalkyl, phenyl, furanyl, thienyl,pyridinyl, thiazolyl, benzothienyl, benzofuranyl, naphthyl, orsubstituted derivatives thereof, wherein the substituents maybe selectedfrom the group consisting of C₁-C₅ alkyl, halogen, CF₃, CN, NO₂, N(R²)₂,CO₂R² and OR²;

[0022] Z is (CH₂)_(n) or a covalent bond;

[0023] R is C₁-C₆ lower alkyl, benzyl, or Z-CF₃ or mesylate or triflate;

[0024] R¹ is H, R² or COR²; and

[0025] R² is H or C₁-C₅ lower alkyl or 9, 11 or 15 esters thereof.

[0026] In a still further aspect, the present invention relates to apharmaceutical product, comprising

[0027] a container adapted to dispense its contents in a metered form;and

[0028] an ophthalmic solution therein, as hereinabove defined.

[0029] Finally, certain of the compounds represented by the aboveformula, disclosed below and utilized in the method of the presentinvention are novel and unobvious.

BRIEF DESCRIPTION OF THE DRAWING FIGURES

[0030]FIG. 1 is a schematic of the chemical synthesis of certaincompounds of the invention as disclosed in Examples 5 and 6.

[0031]FIG. 2 is a schematic of the chemical synthesis of certaincompounds of the invention as disclosed in Examples 39, 41, 43 and 45.

[0032]FIG. 3 is a schematic of the chemical synthesis of certaincompounds of the invention as disclosed in Examples 40, 42, 44 and 46.

[0033]FIG. 4 is a schematic of the chemical synthesis of certaincompounds of the invention as disclosed in Examples 47 and 48.

DETAILED DESCRIPTION OF THE INVENTION

[0034] The present invention relates to the use of cyclopentaneheptan(ene) acyl sulfonamide, 2-alkyl or 2-arylalkyl, or2-heteroarylalkenyl derivatives as therapeutic agents as ocularhypotensives. The compounds used in accordance with the presentinvention are encompassed by the following structural formula I:

[0035] A preferred group of the compounds of the present inventionincludes compounds that have the following structural formula II:

[0036] Another preferred group includes compounds having the formulaIII:

[0037] In the above formulae, the substituents and symbols are ashereinabove defined.

[0038] In the above formula:

[0039] X is preferably CH₂.

[0040] Y is preferably selected from the group consisting of n-propyl,thienyl and halo or lower C₁ to C₄ alkyl substituted derivatives ofthienyl.

[0041] Z is preferably a covalent bond.

[0042] R is preferably selected from the group consisting of methyl,ethyl, n-propyl, n-butyl, benzyl, CF₃, mesylate or triflate.

[0043] R¹ is preferably selected from the group consisting of H, methyl,ethyl, acetyl or pivaloyl.

[0044] R² is preferably H.

[0045] The above compounds of the present invention may be prepared bymethods that are known in the art or according to the working examplesbelow. The compounds, below, are especially preferred representatives,of the compounds of the present invention.

[0046]N-{(Z)-7-[(1R,2R,3R,5S)-3,5-Dihydroxy-2-((S)-(E)-3-hydroxyoct-1-enyl)cyclopentyl]-hept-5-enoyl}methanesulfonamide

[0047] Ethanesulfonic acid{(Z)-7-[(1R,2R,3R,5S)-3,5-dihydroxy-2-((S)-(E)-3-hydroxyoct-1-enyl)cyclopentyl]hept-5-enoyl}amide

[0048] Ethanesulfonic acid{(Z)-7-[(1R,2R,3R,5S)-3,5-dihydroxy-2-((R)-(E)-3-hydroxyoct-1-enyl)cyclopentyl]hept-5-enoyl}amide

[0049] Propane-1-sulfonic acid{(Z)-7-[(1R,2R,3R,5S)-3,5-dihydroxy-2-((S)-(E)-3-hydroxyoct-1-enyl)cyclopentyl]hept-5-enoyl}amide

[0050] Propane-1-sulfonic acid{(Z)-7-[(1R,2R,3R,5S)-3,5-dihydroxy-2-((R)-(E)-3-hydroxyoct-1-enyl)cyclopentyl]hept-5-enoyl}amide

[0051] Butane-1-sulfonic acid{(Z)-7-[(1R,2R,3R,5S)-3,5-dihydroxy-2-((S)-(E)-3-hydroxyoct-1-enyl)cyclopentyl]hept-5-enoyl}amide

[0052] Butane-1-sulfonic acid{(Z)-7-[(1R,2R,3R,5S)-3,5-dihydroxy-2-((R)-(E)-3-hydroxyoct-1-enyl)cyclopentyl]hept-5-enoyl}amide

[0053]N-{(Z)-7-[(1R,2R,3R,5S)-3,5-Dihydroxy-2-((S)-(E)-3-hydroxyoct-1-enyl)cyclopentyl]-hept-5-enoyl}N-methylmetbanesulfonamide

[0054]N-{(Z)-7-[(1R,2R,3R,5S)-3,5-Dihydroxy-2-((S)-(E)-3-hydroxyoct-1-enyl)cyclopentyl]-hept-5-enoyl}N-ethylmethanesulfonamide

[0055]N-{(Z)-7-[(1R,2R,3R,5S)-3,5-Dihydroxy-2-((S)-(E)-3-hydroxy-5-phenylpent-1-enyl)cyclopentyl]-hept-5-enoyl}methanesulfonamide

[0056] 2,2-Dimethylpropionic acid(1R,2R,3R,5S)-4-hydroxy-2-((S)-(E)-3-hydroxyoct-1-enyl)-3-((Z)-7-methanesulfonylamino-7-oxohept-2-enyl)cyclopentylester

[0057]N-{(Z)-7-[(1R,2R,3R,5S)-3,5-Dihydroxy-2-((S)-(E)-3-hydroxyoct-1-enyl)cyclopentyl]-hept-5-enoyl}-1,1,1-trifluoromethanesulfonamide

[0058] N-{(E)-7-[(1R,2R,3R,5S)-3,5-Dihydroxy-2-((S)-(E)-3-hydroxy-5-phenylpent-1-enyl)-cyclopentyl]hept-5-enoyl}methanesulfonamide

[0059] Ethanesulfonic acid((Z)-7-{(1R,2R,3R,5S)-2-[(S)-(E)-5-(4-bromo-5-methylthiophen-2-yl)-3-hydroxypent-1-enyl]-3,5-dihydroxycyclopentyl}hept-5-enoyl)amide

[0060]N-((Z)-7-{(1R,2R,3R,5S)-2-((S)-(E)-5-(5-Bromo-4-methylthiophen-2-yl)-3-hydroxypent-1-enyl)-3,5-dihydroxycyclopentyl]hept-5-enoy}methanesulfonamide

[0061] Ethanesulfonic acid((Z)-7-{(1R,2R,3R,5S)-2-((S)-(E)-5-(5-bromo-4-methylthiophen-2-yl)-3-hydroxypent-1-enyl)-3,5-dihydroxycyclopentyl]hept-5-enoyl}amide

[0062]N-((Z)-7-{(1R,2R,3R,5S)-2-[((S)-(E)-5-(5-Bromo-4-methylthiophen-2-yl)-3-hydroxypent-1-enyl)-3,5-dihydroxycyclopentyl]hept-5-enoyl}-1,1,1-trifluoromethanesulfonamide

[0063]N-((Z)-7-{(1R,2R,3R,5S)-2-[((S)-(E)-5-(4-Chloro-5-methylthiophen-2-yl)-3-hydroxypent-1-enyl)-3,5-dihydroxycyclopentyl]hept-5-enoyl}methanesulfonamide

[0064] Ethanesulfonic acid((Z)-7-{(1R,2R,3R,5S)-2-[((S)-(E)-5-(4-chloro-5-methylthiophen-2-yl)-3-hydroxypent-1-enyl)-3,5-dihydroxycyclopentyl]hept-5-enoyl}amide

[0065] N-((Z)-7-{(1R,2R,3R,5S)-2-[((S)-(E)-5-(4-Chloro-5-methylthiophen-2-yl)-3-hydroxypent-1-enyl)-3,5-dihydroxycyclopentyl]hept-5-enoyl}-1,1,1-trifluoromethanesulfonamide

[0066] N-((Z)-7-{(1R,2R,3R,5S)-3,5-Dihydroxy-2-[((S)-(E)-3-hydroxy-5-(2-methylthiophen-3-yl)pent-1-enyl)cyclopentyl}hept-5-enoyl)methanesulfonamide

[0067] Ethanesulfonic acid((Z)-7-{(1R,2R,3R,5S)-3,5-dihydroxy-2-[((S)-(E)-3-hydroxy-5-(2-methylthiophen-3-yl)pent-1-enyl]cyclopentyl}hept-5-enoyl)amide

[0068]N-((Z)-7-{(1R,2R,3R,5S)-3,5-Dihydroxy-2-[((S)-(E)-3-hydroxy-5-(2-methylthiophen-3-yl)pent-1-enyl]cyclopentyl}hept-5-enoyl)-1,1,1-trifluoromethanesulfonamide

[0069]N-((Z)-7-{(1R,2R,3R,5S)-3,5-Dihydroxy-2-[((S)-(E)-3-hydroxy-5-(2-methylthiophen-3-yl)pent-1-enyl)cyclopentyl}heptanoyl)methanesulfonamide

[0070] Ethanesulfonic acid((Z)-7-{(1R,2R,3R,5S)-3,5-dihydroxy-2-[((S)-(E)-3-hydroxy-5-(2-methylthiophen-3-yl)pent-1-enyl]cyclopentyl}heptanoyl)amide

[0071]N-((Z)-7-{(1R,2R,3R,5S)-3,5-Dihydroxy-2-[((S)-(E)-3-hydroxy-5-(2-methylthiophen-3-yl)pent-1-enyl]cyclopentyl}heptanoyl)-1,1,1-trifluoromethanesulfonamide

[0072]N-((Z)-7-{(1R,2R,3R,5S)-2-[((S)-(E)-5-(5-Chlorothiophen-2-yl)-3-hydroxypent-1-enyl)-3,5-dihydroxycyclopentyl]hept-5-enoyl}methanesulfonamide

[0073] Ethanesulfonic acid ((Z)-7-{(1R,2R,3R,5S)-2-[((S)-(E)-5-(5-chlorothiophen-2-yl)-3-hydroxypent-1-enyl)-3,5-dihydroxycyclopentyl]hept-5-enoyl}amide

[0074]N-((Z)-7-{(R,2R,3R,5S)-2-[((S)-(E)-5-(5-Chlorothiophen-2-yl)-3-hydroxypent—enyl)-3,5-dihydroxycyclopentyl]hept-5-enoyl}-1,1,1-trifluoromethanesulfonamide

[0075]N-((Z)-7-{(1R,2R,3R,5S)-3,5-Dihydroxy-2-[((S)-(E)-3-hydroxy-5-(5-iodothiophen-2-yl)pent-1-enyl)cyclopentyl}heptanoyl)methanesulfonamide

[0076] Ethanesulfonic acid((Z)-7-{(1R,2R,3R,5S)-3,5-dihydroxy-2-[((S)-(E)-3-hydroxy-5-(5-iodothiophen-2-yl)pent-1-enyl]cyclopentyl}heptanoyl)amide

[0077]N-((Z)-7-{(1R,2R,3R,5S)-3,5-Dihydroxy-2-[((S)-(E)-3-hydroxy-5-(5-iodothiophen-2-yl)pent-1-enyl]cyclopentyl}heptanoyl)-1,1,1-trifluoromethanesulfonamide

[0078]N-((Z)-7-{(1R,2R,3R,5S)-2-[((S)-(E)-5-(5-Bromothiophen-2-yl)-3-hydroxypent-1-enyl)-3,5-dihydroxycyclopentyl]hept-5-enoyl}methanesulfonamide

[0079] Ethanesulfonic acid((Z)-7-{(1R,2R,3R,5S)-2-[((S)-(E)-5-(5-bromothiophen-2-yl)-3-hydroxypent-1-enyl)-3,5-dihydroxycyclopentyl]hept-5-enoyl}amide

[0080]N-((Z)-7-{(1R,2R,3R,5S)-2-[((S)-(E)-5-(5-Bromothiophen-2-yl)-3-hydroxypent-1-enyl)-3,5-dihydroxycyclopentyl]hept-5-enoyl}-1,1,1-trifluoromethanesulfonamide

[0081] Acetic acid({(Z)-7-[(1R,2R,3R,5S)-3,5-dihydroxy-2-((S)-(E)-3-hydroxyoct-1-enyl)-cyclopentyl]hept-5-enoyl}methanesulfonylamino)methylester

[0082] 2,2-Dimethylpropionic acid({(Z)-7-[(1R,2R,3R,5S)-3,5-dihydroxy-2-((S)-(E)-3-hydroxyoct-1-enyl)-cyclopentyl]hept-5-enoyl}methanesulfonylamino)methylester

[0083] Acetic acid[((Z)-7-{(1R,2R,3R,5S)-2-[((S)-(E)-5-(5-bromo-4-methylthiophen-2-yl)-3-hydroxypent-1-enyl)-3,5-dihydroxycyclopentyl}hept-5-enoyl)methanesulfonyl-amino]methyl ester

[0084] 2,2-Dimethylpropionic acid [((Z)-7-{(1R,2R,3R,5S)-2-[((S)-(E)-5-(5-bromo-4-methylthiophen-2-yl)-3-hydroxypent-1-enyl)-3,5-dihydroxycyclopentyl}hept-5-enoyl)methanesulfonyl-amino]methyl ester

[0085] Acetic acid[((Z)-7-{(1R,2R,3R,5S)-2-[((S)-(E)-5-(4-chloro-5-methylthiophen-2-yl)-3-hydroxypent-1-enyl)-3,5-dihydroxycyclopentyl}hept-5-enoyl)methanesulfonyl-amino]methyl ester

[0086] 2,2-Dimethylpropionic acid[((Z)-7-{(1R,2R,3R,5S)-2-[((S)-(E)-5-(4-chloro-5-methyl-thiophen-2-yl)-3-hydroxypent-1-enyl)-3,5-dihydroxycyclopentyl}hept-5-enoyl)methane-sulfonyl-amino]methyl ester

[0087] Acetic acid [((Z)-7-{(1R,2R,3R,5S)-2-[((S)-(E)-5-(5-bromothiophen-2-yl)-3-hydroxypent-1-enyl)-3,5-dihydroxycyclopentyl}hept-5-enoyl)methanesulfonylamino]methylester

[0088] 2,2-Dimethylpropionic acid[((Z)-7-{(1R,2R,3R,5S)-2-[((S)-(E)-5-(5-bromothiophen-2-yl)-3-hydroxypent-1-enyl)-3,5-dihydroxycyclopentyl}hept-5-enoyl)methanesulfonyl-amino]methyl ester

[0089]{3-[(1R,2S,3R)-3-Hydroxy-2-((S)-(E)-3-hydroxyoct-1-enyl)-5-oxocyclopentylsulfanyl]propylsulfanyl}aceticacid methyl ester

[0090]{3-[(1R,2S,3R)-3-Hydroxy-2-((S)-(E)-3-hydroxyoct-1-enyl)-5-oxocyclopentylsulfanyl]propylsulfanyl}aceticacid

[0091]{3-[(1R,2S,3R)-3-Hydroxy-2-((S)-(E)-3-hydroxyoct-1-enyl)-5-oxocyclopentylsulfanyl]propylsulfanyl}aceticacid isopropyl ester

[0092](3-{(1R,2S,3R)-3-Hydroxy-2-[(E)-4-hydroxy-4-(1-propylcyclobutyl)but-1-enyl]-5-oxocyclopentylsulfanyl}propylsulfanyl)aceticacid methyl ester

[0093](3-{(1R,2S,3R)-3-Hydroxy-2-[(E)-4-hydroxy-4-(1-propylcyclobutyl)but-1-enyl]-5-oxocyclopentylsulfanyl}propylsulfanyl)aceticacid

[0094]N-{(Z)-7-[(1R,2R,3R,5S)-3,5-Dihydroxy-2-((S)-(E)-3-hydroxyoct-1-enyl)cyclopentyl]-hept-5-enoyl}benzenesulfonamide

[0095]N-((Z)-7-{(1R,2R,3R,5S)-2-[((S)-(E)-5-(4-Chloro-5-methylthiophen-2-yl)-3-hydroxypent-1-enyl)-3,5-dihydroxycyclopentyl]hept-5-enoyl}benzenesulfonamide

[0096] Pharmaceutical compositions may be prepared by combining atherapeutically effective amount of at least one compound according tothe present invention, or a pharmaceutically acceptable acid additionsalt thereof, as an active ingredient, with conventional ophthalmicallyacceptable pharmaceutical excipients, and by preparation of unit dosageforms suitable for topical ocular use. The therapeutically efficientamount typically is between about 0.0001 and about 5% (w/v), preferablyabout 0.001 to about 1.0% (w/v) in liquid formulations.

[0097] For ophthalmic application, preferably solutions are preparedusing a physiological saline solution as a major vehicle. The pH of suchophthalmic solutions should preferably be maintained between 6.5 and 7.2with an appropriate buffer system. The formulations may also containconventional, pharmaceutically acceptable preservatives, stabilizers andsurfactants.

[0098] Preferred preservatives that may be used in the pharmaceuticalcompositions of the present invention include, but are not limited to,benzalkonium chloride, chlorobutanol, thimerosal, phenylmercuric acetateand phenylmercuric nitrate. A preferred surfactant is, for example,Tween 80. Likewise, various preferred vehicles may be used in theophthalmic preparations of the present invention. These vehiclesinclude, but are not limited to, polyvinyl alcohol, povidone,hydroxypropyl methyl cellulose, poloxamers, carboxymethyl cellulose,hydroxyethyl cellulose and purified water.

[0099] Tonicity adjustors may be added as needed or convenient. Theyinclude, but are not limited to, salts, particularly sodium chloride,potassium chloride, mannitol and glycerin, or any other suitableophthalmically acceptable tonicity adjustor.

[0100] Various buffers and means for adjusting pH may be used so long asthe resulting preparation is ophthalmically acceptable. Accordingly,buffers include acetate buffers, citrate buffers, phosphate buffers andborate buffers. Acids or bases may be used to adjust the pH of theseformulations as needed.

[0101] In a similar vein, an ophthalmically acceptable antioxidant foruse in the present invention includes, but is not limited to, sodiummetabisulfite, sodium thiosulfate, acetylcysteine, butylatedhydroxyanisole and butylated hydroxytoluene.

[0102] Other excipient components which may be included in theophthalmic preparations are chelating agents. The preferred chelatingagent is edentate disodium, although other chelating agents may also beused in place or in conjunction with it.

[0103] The ingredients are usually used in the following amounts:Ingredient Amount (% w/v) active ingredient about 0.001-5 preservative0-0.10 vehicle 0-40 tonicity adjustor 1-10 buffer 0.01-10 pH adjustorq.s. pH 4.5-7.5 antioxidant as needed surfactant as needed purifiedwater as needed to make 100%

[0104] The actual dose of the active compounds of the present inventiondepends on the specific compound, and on the condition to be treated;the selection of the appropriate dose is well within the knowledge ofthe skilled artisan.

[0105] The ophthalmic formulations of the present invention areconveniently packaged in forms suitable for metered application, such asin containers equipped with a dropper, to facilitate the application tothe eye. Containers suitable for dropwise application are usually madeof suitable inert, non-toxic plastic material, and generally containbetween about 0.5 and about 15 ml solution.

[0106] The invention is further illustrated by the followingnon-limiting Examples, which are summarized in the reaction schemes ofFIGS. 1 through 3 wherein the compounds are identified by the samedesignator in both the Examples and the Figures.

EXAMPLE 1

[0107]N-{(Z)-7-[(1R,2R,3R,5S)-3,5-Dihydroxy-2-((S)-(E)-3-hydroxyoct-1-enyl)cyclopentyl]-hept-5-enoyl}methanesulfonamide

[0108] Prepared in accordance with the procedures described in Schaaf,T. K., Hess, H. -J. J. Med. Chem. 1979, 22, 1340-1346.

[0109] Alternatively, the title compound could be synthesized fromtris-THP-prostaglandin F₂, methyl ester as follows (see Scheme 1):

[0110] Step 1: Saponification of the Ester

[0111] Lithium hydroxide (6.8 mL of a 1.0 N solution in H₂O, 6.8 mmol)was added to a solution of tris-THP-prostaglandin F₂, methyl ester (1.05g, 1.69 mmol) in THF (16 mL). After stirring 18 h at room temperaturethe reaction mixture was concentrated in vacuo. The residue was dilutedwith H₂O, acidified with 1 N HCl and extracted with CH₂Cl₂ (2×). Thecombined extracts were washed with brine, dried (Na₂SO₄) filtered andconcentrated in vacuo. Purification by flash column chromatography(silica gel, 33% EtOAc/Hex) afforded 940 mg (92%) of tris-THP PGF_(2α).

[0112] Step 2: Preparation of the Tris-THP Acylsulfonamide

[0113] Tris-THP PGF_(2α) (495 mg, 0.816 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) (220mg, 1.15 mmol), 4-dimethyl-aminopyridine (DMAP) (125 mg, 1.02 mmol) andmethanesulfonamide (235 mg, 2.47 mmol) were dissolved in DMF (3.4 mL)and the resulting solution was stirred at room temperature under anatmosphere of nitrogen. After 16 h the solution was diluted with EtOAcand washed with 1 N aqueous HCl (3×) and brine (1×), then dried(Na₂SO₄), filtered and concentrated in vacuo. Purification by flashcolumn chromatography (silica gel, 45% EtOAc/Hex) afforded 468 mg (84%)of tris-THP PGF_(2α) methanesulfonamide.

[0114] Step 3: Deprotection of the Tris-THP Acylsulfonamide

[0115] Pyridiniump-toluenesulfonate (PPTs) (20 mg, 0.080 mmol) was addedto a solution of tris-THP PGF_(2α) methanesulfonamide (468 mg, 0.684mmol) in MeOH (6.5 mL). The solution was heated at 45° C. under anatmosphere of nitrogen. After 16 h, the reaction mixture was cooled thenconcentrated in vacuo to afford a crude oil. Flash column chromatography(silica gel, EtOAc, then 2% MeOH in EtOAc) gave 152 mg (51%) of thetitle compound.

EXAMPLE 2

[0116] Ethanesulfonic Acid{(Z)-7-[(1R,2R,3R,5S)-3,5-Dihydroxy-2-((S)-(E)-3-hydroxyoct-1-enyl)cyclopentyl]hept-5-enoyl}amideand Ethanesulfonic Acid{(Z)-7-[(1R,2R,3R,5S)-3,5-Dihydroxy-2-((R)-(E)-3-hydroxyoct-1-enyl)cyclopentyl]hept-5-enoyl}amide

[0117] The title compounds were prepared in accordance with theprocedures described in Schaaf, T. K., Hess, H. -J. J. Med. Chem. 1979,22, 1340-1346, with the following exceptions: methanesulfonamide wasreplaced with ethanesulfonamide; the bicyclic lactol was used as a 1:1mixture of epimeric 15R and 15S alcohols (prostaglandin numbering used,see Scheme 2); the 15R and 15S alcohols were separated duringchromatography at the end of the synthetic sequence to afford the titlecompounds.

EXAMPLE 3

[0118] Propane-1-sulfonic Acid{(Z)-7-[(1R,2R,3R,5S)-3,5-Dihydroxy-2-((S)-(E)-3-hydroxyoct-1-enyl)cyclopentyl]hept-5-enoyl}amideand Propane-1-sulfonic Acid{(Z)-7-[(1R,2R,3R,5S)-3,5-Dihydroxy-2-((R)-(E)-3-hydroxyoct-1-enyl)cyclopentyl]hept-5-enoyl}amide

[0119] The title compounds were prepared in accordance with theprocedures described in Schaaf, T. K., Hess, H. -J. J. Med. Chem. 1979,22, 1340-1346, with the following exceptions: methanesulfonamide wasreplaced with propane-1-sulfonamide; the bicyclic lactol was used as a1:1 mixture of epimeric 15R and 15S alcohols (prostaglandin numberingused, see Scheme 2); the 15R and 15S alcohols were separated duringchromatography at the end of the synthetic sequence to afford the titlecompounds.

EXAMPLE 4

[0120] Butane-1-sulfonic Acid {(Z)-7-[(1R,2R,3R,5S)-3,5-Dihydroxy-2-((S)-(E)-3-hydroxyoct-1-enyl)cyclopentyl]hept-5-enoyl}amideand Butane-1-sulfonic Acid {(Z)-7-[(1R,2R,3R,5S)-3,5-Dihydroxy-2-((R)-(E)-3-hydroxyoct-1-enyl)cyclopentyl]hept-5-enoyl}amide

[0121] The title compounds were prepared in accordance with theprocedures described in Schaaf, T. K., Hess, H. -J. J. Med. Chem. 1979,22, 1340-1346, with the following exceptions: methanesulfonamide wasreplaced with butane-1-sulfonamide; the bicyclic lactol was used as a1:1 mixture of epimeric 15R and 15S alcohols (prostaglandin numberingused, see Scheme 2); the 15R and 15S alcohols were separated duringchromatography at the end of the synthetic sequence to afford the titlecompounds.

EXAMPLE 5

[0122]N-{(Z)-7-[(1R,2R,3R,5S)-3,5-Dihydroxy-2-((S)-(E)-3-hydroxyoct-1-enyl)cyclopentyl]-hept-5-enoyl}-N-methylmethanesulfonamide

[0123] Methyl iodide (38 μL, 0.61 mmol) and DBU (45 μL, 0.30 mmol) wereadded to a solution ofN-{(Z)-7-[(1R,2R,3R,5S)-3,5-Dihydroxy-2-((S)-(E)-3-hydroxyoct-1-enyl)cyclopentyl]hept-5-enoyl}methanesulfonamide(44 mg, 0.10 mmol) in acetone (1.5 mL). After stirring for 2.5 h at roomtemperature, the reaction was diluted with EtOAc, washed with water (2×)and brine then concentrated in vacuo to afford the title compound. SeeFIG. 1.

EXAMPLE 6

[0124]N-{(Z)-7-[(1R,2R,3R,5S)-3,5-Dihydroxy-2-((S)-(E)-3-hydroxyoct-1-enyl)cyclopentyl]-hept-5-enoyl}-N-ethylmethanesulfonamide

[0125] The title compound was prepared in accordance with the procedureof example 5, replacing methyl iodide with ethyl iodide.

EXAMPLE 7

[0126]N-{(Z)-7-[(1R,2R,3R,5S)-3,5-Dihydroxy-2-((S)-(E)-3-hydroxy-5-phenylpent-1-enyl)cyclopentyl]hept-5-enoyl}methanesulfonamide

[0127] Step 1: Global Silylation of 17-Phenyl PGF_(2α)

[0128] 2,6-Lutidine (0.940 mL, 8.07 mmol) and tert-butyldimethylsilylchloride (1.22 g, 8.07 mmol) were added to a solution of 17-phenylPGF_(2α) (521 mg, 1.34 mmol) in DMF (13.4 mL). After stirring overnightat room temperature, the reaction was diluted with EtOAc then washedwith water (3×) and brine (2×) and concentrated in vacuo. Purificationof the residue by flash column chromatography (silica gel, 5% EtOAc/Hex)afforded 1.06 g (93%) of tetra-TBDMS-17-phenyl PGF_(2α).

[0129] Step 2: Preparation of the Tris-TBDMS Acid

[0130] A solution of potassium carbonate (345 mg, 2.50 mmol) in H₂O (3.5mL) was added to a solution of tetra-TBDMS-17-phenyl PGF_(2α) (1.06 g,1.25 mmol) in MeOH (15.6 mL) and THF (5.2 mL). After 1 h, the reactionmixture was acidified with 1 N HCl and extracted with CH₂Cl₂ (3×). Thecombined extracts were dried (Na₂SO₄), filtered and concentrated invacuo to afford 912 mg (100%) of tris-TBDMS-17-phenyl PGF_(2α).

[0131] Step 3: Preparation of the Tris-TBDMS Acylsulfonamide

[0132] Methanesulfonamide (519 mg, 6.25 mmol), DMAP (153 mg, 1.25 mmol)and DCC (1.29 g, 6.25 mmol) were added to a solution oftris-TBDMS-17-phenyl PGF_(2α) (912 mg, 1.25 mmol) in CH₂Cl₂ (100 mL).The solution was stirred at room temperature overnight, thenconcentrated in vacuo. The residue was diluted with EtOAc and the solidurea by-product was removed by filtration. The filtrate was concentratedin vacuo and the residue was purified twice by flash columnchromatography (silica gel, 25% EtOAc/Hex) to afford 176 mg (17%) of thetris-TBDMS acylsulfonamide.

[0133] Step 4: Desilylation of the Tris-TBDMS Acylsulfonamide

[0134] Hydrogen fluoride-pyridine (288 μL) was added to a solution ofthe compound obtained in step 1 above (176 mg, 0.241 mmol) in THF (3.6mL) at 0° C. under N₂. After 2 h, additional HF-pyridine (288 μL) wasadded and stirring was continued at 0° C. After 1 h, additionalHF-pyridine (288 μL) was added and stirring was continued at 0° C. for40 min, then the reaction mixture was allowed to warm to roomtemperature. The solution was then diluted with EtOAc and neutralizedwith saturated NaHCO₃. The layers were separated and the aqueous phasewas extracted with CHCl₃ (2×). The combined organic layers wereconcentrated in vacuo. The residue was purified by flash chromatography(silica gel, 5% MeOH/EtOAc) to afford 22 mg (20%) of the title compound.This method of this Example is shown in Scheme 3.

EXAMPLE 8

[0135]N-{(Z)-7-[(1R,2R,3R,5S)-3,5-Dihydroxy-2-((S)-(E)-3-hydroxyoct-1-enyl)cyclopentyl]-hept-5-enoyl}-1,1,1-trifluoromethanesulfonamide

[0136] Step 1: Global Silylation of PGF_(2α)

[0137] In accordance with the procedure described in example 7, step 1,the use of PGF_(2α) gave tetra-TBDMS-PGF_(2α)

[0138] Step 2: Preparation of the Tris-TBDMS Acid

[0139] In accordance with the procedure described in example 7, step 2,the use of tetra-TBDMS-PGF₂,gave tris-TBDMS-PGF_(2α).

[0140] Step 3: Preparation of the Tris-TBDMS Acylsulfonamide

[0141] In accordance with the procedure described in example 7, step 3,the use of tris-TBDMS-PGF₂, and trifluoromethanesulfonamide affordedtris-TBDMS-PGF₂. trifluoromethanesulfonamide.

[0142] Step 4: Desilylation of the Tris-TBDMS Acylsulfonamide

[0143] In accordance with the procedure described in example 7, step 4,the use of tris-TBDMS-PGF₂, trifluoromethanesulfonamide gave the titlecompound.

EXAMPLE 9

[0144] 2,2-Dimethylpropionic Acid(1R,2R,3R,4S)-4-hydroxy-2-((S)-(E)-3-hydroxyoct-1-enyl)-3-((Z)-7-methanesulfonamino-7-oxohept-2-enyl)cyclopentylEster

[0145] Step 1: Preparation of 11-Pivaloyl PGF_(2α) Methyl Ester

[0146] Pyridine (2.3 mL, 28.5 mmol) and trimethylacetyl chloride (879μL, 7.14 mmol) were added to a solution of PGF₂, methyl ester (2.63 g,7.14 mmol) in CH₂Cl₂ (100 mL) at 0° C. After 2 h, the reaction wasallowed to warm to room temperature. After another 1.5 h, the solutionwas washed with 10% citric acid (2×) and brine then concentrated invacuo. The crude residue was purified by flash column chromatography(silica gel, 30% EtOAc/Hex) to afford 1.27 g (41%) of 11-PivaloylPGF_(2α) methyl ester.

[0147] Step 2: Preparation of 9,15-bis-TBDMS-11-PivaloylPGF_(2α) MethylEster

[0148] 2,6-Lutidine (1.36 mL, 11.6 mmol) and tert-butyldimethylsilylchloride (1.75 g, 11.6 mmol) were added to a solution of 11-PivaloylPGF₂, methyl ester (1.27 g, 2.91 mmol) in DMF (30 mL). After stirringovernight at room temperature, the reaction was diluted with EtOAc thenwashed with water (3×) and brine and concentrated in vacuo. Purificationof the residue by flash column chromatography (silica gel, 10%EtOAc/Hex) afforded 1.84 g (95%) of 9,15-bis-TBDMS-11-Pivaloyl PGF_(2α)methyl ester.

[0149] Step 3: Saponification of 9,15-bis-TBDMS-11-Pivaloyl PGF_(2α)Methyl Ester

[0150] Lithium hydroxide (5.5 mL of a 0.5 N solution in H₂O, 2.75 mmol)was added to a solution of 9,15-bis-TBDMS-11-Pivaloyl PGF_(2α) methylester (1.82 g, 2.73 mmol) in THF (5.5 mL) and the solution was heated at50° C. overnight. The reaction mixture was cooled and acidified with 10%aqueous HCl, then extracted with CHCl₃ (3×). The extracts wereconcentrated in vacuo affording 949 mg (53%) of9,15-bis-TBDMS-11-Pivaloyl PGF_(2α).

[0151] Step 4: Preparation of 9,15-bis-TBDMS-11-Pivaloyl PGF_(2α)Methanesulfonamide

[0152] In accordance with the procedure described above for example 7,step 3, the use of 9,15-bis-TBDMS-11-Pivaloyl PGF₂a gave9,15-bis-TBDMS-11-Pivaloyl PGF_(2α) methanesulfonamide.

[0153] Step 5: Desilylation of 9,15-bis-TBDMS-11-Pivaloyl PGF_(2α)Methanesulfonamide

[0154] In accordance with the procedure described in example 7, step 4,the use of 9,15-bis-TBDMS-11-Pivaloyl PGF_(2α) methanesulfonamide gavethe title compound. The method of this Example is shown in Scheme 4.

EXAMPLE 10

[0155]N-{(E)-7-[(1R,2R,3R,5S)-3,5-Dihydroxy-2-((S)-(E)-3-hydroxy-5-phenylpent-1-enyl)cyclopentyl]hept-5-enoyl}methanesulfonamide

[0156] Step 1: Preparation of tris-TBDMS-17-phenyl PGF_(2α) Methyl Ester

[0157] 2,6-Lutidine (2.27 mL, 19.5 mmol) and tert-butyldimethylsilylchloride (2.94 g, 19.5 mmol) were added to a solution of 17-phenylPGF_(2α) methyl ester (1.30 g, 3.25 mmol) in DMF (32.5 mL). Afterstirring overnight at room temperature, the reaction was diluted withEtOAc then washed with water (3×) and brine and concentrated in vacuo.Purification of the residue by flash column chromatography (silica gel,5% EtOAc/Hex) afforded 1.86 g (77%) of tris-TBDMS-17-phenyl PGF_(2α)methyl ester.

[0158] Step 2: Preparation of 5-(E)-tris-TBDMS-17-phenyl PGF_(2α) MethylEster

[0159] Phenyl disulfide (54 mg, 0.25 mmol) was added to a solution oftris-TBDMS-17-phenyl PGF₂. methyl ester (1.86 g, 2.5 mmol) in benzene(20 mL). The solution was irradiated overnight, then concentrated invacuo to afford 5-(E)-tris-TBDMS-17-phenyl PGF_(2α) methyl ester, whichwas used without further purification.

[0160] Step 3: Saponification of 5-(E)-tris-TBDMS-17-phenyl PGF_(2α)Methyl Ester

[0161] Lithium hydroxide (5.0 mL of a 0.5 N solution in H₂O, 2.5 mmol)was added to a solution of 5-(E)-tris-TBDMS-17-phenyl PGF_(2α) methylester (879 mg, 1.18 mmol) in THF (5.0 mL). The solution was heated to50° C. overnight. The reaction mixture was cooled and acidified with 3 NHCl then extracted with CHCl₃ (3×). The extracts were concentrated invacuo to afford 5-(E)-tris-TBDMS-17-phenyl PGF_(2α) which was usedwithout further purification.

[0162] Step 4: Preparation of 5-(E)-tris-TBDMS-17-phenyl PGF_(2α)Acylsulfonamide

[0163] In accordance with the procedure described in example 7, step 3,the use of 5-(E)-tris-TBDMS-17-phenyl PGF₂. afforded5-(E)-tris-TBDMS-17-phenyl PGF_(2α) acylsulfonamide

[0164] Step 5: Desilylation of 5-(E)-tris-TBDMS-17-phenyl PGF_(2α)Acylsulfonamide

[0165] In accordance with the procedure described in example 7, step 4,the use of 5-(E)-tris-TBDMS-17-phenyl PGF_(2α) acylsulfonamide gave thetitle compound. The method of the Example is shown in Scheme 5.

EXAMPLE 11

[0166](Z)-7-[(1R,2R,3R,5S)-2-[(S)-(E)-5-(5-Bromo-4-methylthiophen-2-yl)-3-(tetrahydropyran-2-yloxy)pent-1-enyl]-3,5-bis(tetrahydropyran-2-yloxy)cyclopentyl]hept-5-enoicAcid (5a)

[0167] Step 1: Preparation of Enone 2a

[0168] To a suspension of sodium hydride (60% oil dispersion, 100 mg,2.50 mmol) in THF (6 mL) at 0° C. was added a solution of dimethyl4-(5-(2-bromo-3-methyl)thienyl)-2-oxobutylphosphonate (856 mg, 2.41mmol) in THF (4 mL+2 mL). After 15 min at 0° C., a solution of aldehyde1 (877 mg, 2.01 mmol) in THF (4 mL+2 mL) was added. After 30 min at 0°C., the reaction was allowed to warm to room temperature. After 2 h atroom temperature, the reaction was quenched with saturated aqueous NH₄Cland extracted with EtOAc. The organic phase was washed with saturatedaqueous NaHCO₃ and brine, then dried (MgSO₄), filtered and concentratedin vacuo. Purification of the residue by flash column chromatography(silica gel, 25% EtOAc/Hex) gave 1.15 g (86%) of enone 2a.

[0169] Step 2: Preparation of 15S Alcohol (3a)

[0170] Absolute ethanol (3.75 mL of a 1.0 M solution in THF, 3.75 mmol)was slowly added to a solution of lithium aluminum hydride (3.75 mL of a1.0 M solution in THF, 3.75 mL). A solution of (S)-1,1′-bi-2-naphthol(1.08 g, 3.77 mmol) in THF (15 mL) was then added dropwise. After 30min, a cloudy heterogeneous mixture persisted.

[0171] The freshly prepared BINAl—H mixture was cooled to −85° C., thena solution of enone 2a (500 mg, 0.75 mmol) in THF (15 mL) was addeddropwise. After 1 h at −85° C., the reaction mixture was warmed to −78°C. After 1 h at −78° C., the reaction was quenched with methanol,allowed to warm to room temperature and then 1 N HCl was added. THF wasremoved by concentration in vacuo, then the aqueous remainder wasextracted with EtOAc (2×). The combined extracts were washed with brinethen dried (Na₂SO₄), filtered and concentrated in vacuo. The residuedissolved in CH₂Cl₂, then (S)-1,1′-bi-2-naphthol was precipitated byaddition of hexane. The solid was removed by filtration (800 mg of(S)-1,1′-bi-2-naphthol was recovered) and the filtrate was concentratedin vacuo. Purification of the residue by flash column chromatography(silica gel, 25% EtOAc/Hex) gave 215 mg (43%) of alcohol 3a.

[0172] Step 3: Preparation of Tris-THP Ester (4a)

[0173] Dihydropyran (300 μL, 3.29 mmol) and PPTs (25 mg, 0.10 mmol) wereadded sequentially to a solution of alcohol 3a (755 mg, 1.13 mmol) inCH₂Cl₂ (4 mL). The reaction mixture was stirred overnight at roomtemperature, then concentrated in vacuo. The residue was diluted withEtOAc, washed with 1 N HCl, water, saturated aqueous NaHCO₃ and brine,then dried (MgSO₄), filtered and concentrated in vacuo. The resultingproduct 4a was taken on without further purification. If desired,further purification by flash column chromatography (silica gel, 25%EtOAc/Hex) could be carried out.

[0174] Step 4: Saponification of Ester (4a)

[0175] Lithium hydroxide (4.5 mL of a 1.0 N solution in water, 4.5 mmol)was added to a solution of ester 4a (approx 1.13 mmol) in THF (11 mL).The reaction was stirred overnight at room temperature then concentratedin vacuo. The aqeous remainder was diluted with water then acidifiedwith 1 N HCl and extracted with CH₂Cl₂ (2×). The combined extracts werewashed with brine, dried (Na₂SO₄), filtered and concentrated in vacuo.Purification of the residue by flash column chromatography (silica gel,40% EtOAc/Hex) gave 750 mg (90%) of acid 5a. The method of this Exampleis shown in Scheme 6.

EXAMPLE 12

[0176](Z)-7-[(1R,2R,3R,5S)-2-[(S)-(E)-5-(4-Chloro-5-methylthiophen-2-yl)-3-(tetrahydropyran-2-yloxy)pent-1-enyl]-3,5-bis(tetrahydropyran-2-yloxy)cyclopentyl]hept-5-enoicAcid (5b)

[0177] In accordance with the procedures described above for thesynthesis of 5a, the use of dimethyl4-(5-(3-chloro-2-methyl)thienyl)-2-oxobutylphosphonate gave acid 5b.

EXAMPLE 13

[0178](Z)-7-[(1R,2R,3R,5S)-2-[(S)-(E)-5-(5-Chlorothiophen-2-yl)-3-(tetrahydropyran-2-yloxy)pent-1-enyl]-3,5-bis(tetrahydropyran-2-yloxy)cyclopentyl]hept-5-enoicAcid (5c)

[0179] The synthesis of 5c was carried out in accordance with theprocedures described above for the synthesis of 5a, with the followingexceptions: dimethyl 4-(5-(2-chloro)thienyl)-2-oxobutylphosphonate) wasused in place of dimethyl4-(5-(2-bromo-3-methyl)thienyl)-2-oxobutylphosphonate and a differentreduction method was used in step 2, as described below.

[0180] Step 2: Preparation of the 15S Alcohol (3c)

[0181] Sodium borohydride (85 mg, 2.25 mmol) was added in one portion toa solution of enone 2c (1.32 g, 2.17 mmol) in MeOH (21 mL) at 0° C.After 3 h, the reaction was concentrated in vacuo then partitionedbetween saturated aqueous NH₄Cl and EtOAc. The phases were separated andthe aqueous phase was extracted with EtOAc. The combined organic phaseswere dried (MgSO₄), filtered and concentrated in vacuo. Purification ofthe residue by flash column chromatography (3×, silica gel, 25%EtOAc/Hex) afforded 335 mg (25%) of the faster eluting 15R alcohol and183 mg (14%) of 3c.

EXAMPLE 14

[0182] (Z)-7-[(1R,2R,3R,5S)-2-[(S)-(E)-5-(5-Iodothiophen-2-yl)-3-(tert-butyldimethylsilanyloxy)pent-1-enyl]-3,5-bis(tetrahydropyran-2-yloxy)cyclopentyl]hept-5-enoicAcid (5d)

[0183] In accordance with the procedures described above for thesynthesis of 5a, the use of dimethyl4-(5-(2-iodo)thienyl)-2-oxobutylphosphonate gave enone 2d and alcohol 3d(steps 1 and 2, respectively). Further manipulation of alcohol 3d is asfollows:

[0184] Step 3: Preparation of 15-TBDMS-bis-THP 4d

[0185] tert-Butyldimethylsilyl triflate (0.70 mL, 3.06 mmol) was addedto a solution of alcohol 3d (718 mg, 1.02 mmol) and 2,6-lutidine (0.60mL, 5.11 mmol) in CH₂Cl₂ (6.0 mL) at 0° C. The reaction was warmed toroom temperature and stirred for 12 h. The reaction was quenched with 1N NaOH and extracted with EtOAc. The organic phase was washed with 1 NHCl, saturated aqueous NaHCO₃ and brine then dried (MgSO₄), filtered andconcentrated in vacuo. Purification of the residue by flash columnchromatography (20% EtOAc/Hex) afforded 613 mg (74%) of 4d.

[0186] Step 4: Saponification of Ester 4d

[0187] In accordance with the procedure described above for thesynthesis of 5a, ester 4d gave acid 5d. The method of this Example isshown in Scheme 7.

EXAMPLE 15

[0188] (Z)-7-[(1R,2R,3R,5S)-2-[(S)-(E)-5-(5-Bromothiophen-2-yl)-3-(tetrahydropyran-2-yloxy)pent-1-enyl]-3,5-bis(tetrahydropyran-2-yloxy)cyclopentyl]hept-5-enoicAcid (5e)

[0189] In accordance with the procedures described above for thesynthesis of 5a, the use of dimethyl4-(5-(2-bromo)thienyl)-2-oxobutylphosphonate gave acid 5e.

EXAMPLE 16

[0190](Z)-7-[(1R,2R,3R,5S)-2-[(S)-(E)-5-(2-Methylthiophen-3-yl)-3-(tetrahydropyran-2-yloxy)pent-1-enyl]-3,5-bis(tetrahydropyran-2-yloxy)cyclopentyl]hept-5-enoicAcid (5f)

[0191] In accordance with the procedures described above for thesynthesis of 5a, the use of dimethyl4-(3-(2-methyl)thienyl)-2-oxobutylphosphonate gave acid 5f.

EXAMPLE 17

[0192]N-((Z)-7-{(1R,2R,3R,5S)-2-[(S)-(E)-5-(5-Bromo-4-methylthiophen-2-yl)-3-hydroxypent-1-enyl]-3,5-dihydroxycyclopentyl}hept-5-enoyl)methanesulfonamide(9a)

[0193] Step 1: Preparation of the Tris-THP Acylsulfonamide (6a)

[0194] Acid 5a (100 mg, 0.135 mmol), EDCI (36 mg, 0.19 mmol), DMAP (20mg, 0.16 mmol) and methanesulfonamide (39 mg, 0.41 mmol) were dissolvedin DMF (0.6 mL) and the resulting solution was stirred at roomtemperature under an atmosphere of nitrogen. After 15 h the solution wasdiluted with EtOAc and washed with 1 N aqueous HCl (3×) and brine (1×),then dried (Na₂SO₄), filtered and concentrated in vacuo. The crudeproduct (6a), judged to be>90% pure by ¹H NMR, was used directly in thenext step.

[0195] Step 2: Deprotection of the Tris-THP Acylsulfonamide (6a)

[0196] A solution of 6a (approx. 0.135 mmol) in MeOH (1. 1 mL) wastreated with PPTs (4 mg, 0.016 mmol). The solution was heated at 45° C.under an atmosphere of nitrogen. After 16 h, the reaction mixture wascooled then concentrated in vacuo to afford a crude oil. Flash columnchromatography (silica gel, EtOAc, then 2% MeOH in EtOAc) gave 24 mg(31% for 2 steps) of 9a. The method of this Example is shown in Scheme8.

EXAMPLE 18

[0197] Ethanesulfonic Acid((Z)-7-{(1R,2R,3R,5S)-2-[(S)-(E)-5-(5-bromo-4-methylthiophen-2-yl)-3-hydroxypent-1-enyl]-3,5-dihydroxycyclopentyl}hept-5-enoyl)amide(10a)

[0198] Step 1: Preparation of the Tris-THP Acylsulfonamide (7a)

[0199] Acid 5a (100 mg, 0.135 mmol), EDCI (36 mg, 0.19 mmol), DMAP (20mg, 0.16 mmol) and ethanesulfonamide (45 mg, 0.41 mmol) were dissolvedin DMF (0.6 mL) and the resulting solution was stirred at roomtemperature under an atmosphere of nitrogen. After 24 h the solution wasdiluted with EtOAc and washed with 1 N aqueous HCl (3×) and brine (1×),then dried (Na₂SO₄), filtered and concentrated in vacuo. The crudeproduct (7a), judged to be>90% pure by ¹H NMR, was used directly in thenext step.

[0200] Step 2: Deprotection of the Tris-THP Acylsulfonamide (7a)

[0201] A solution of 7a (approx. 0.135 mmol) in MeOH (1.1 mL) wastreated with PPTs (4 mg, 0.016 mmol). The solution was heated at 45° C.under an atmosphere of nitrogen. After 16 h, the reaction mixture wascooled then concentrated in vacuo to afford a crude oil. Flash columnchromatography (silica gel, EtOAc, then 2% MeOH in EtOAc) gave 20 mg(26% for 2 steps) of 10a. The method of this Example is also shown inScheme 8.

EXAMPLE 19

[0202]N-((Z)-7-{(1R,2R,3R,5S)-2-[(S)-(E)-5-(5-Bromo-4-methylthiophen-2-yl)-3-hydroxypent-1-enyl]-3,5-dihydroxycyclopentyl}hept-5-enoyl)-1,1,1-trifluoromethanesulfonamide(11 a)

[0203] Step 1: Preparation of the Tris-THP Acylsulfonamide (8a)

[0204] Acid 5a (100 mg, 0.135 mmol), EDCI (36 mg, 0.19 mmol), DMAP (20mg, 0.16 mmol) and trifluoromethanesulfonamide (61 mg, 0.41 mmol) weredissolved in DMF (0.6 mL) and the resulting solution was stirred at roomtemperature under an atmosphere of nitrogen. After 15 h the solution wasdiluted with EtOAc and washed with IN aqueous HCl (3×) and brine (1×),then dried (Na₂SO₄), filtered and concentrated in vacuo. The crudeproduct (8a), judged to be>90% pure by ¹H NMR, was used directly in thenext step.

[0205] Step 2: Deprotection of the Tris-THP Acylsulfonamide (8a)

[0206] A solution of 8a (approx. 0.135 mmol) in MeOH (1.1 mL) wastreated with PPTs (4 mg, 0.016 mmol). The solution was heated at 45° C.under an atmosphere of nitrogen. After 16 h, the reaction mixture wascooled then concentrated in vacuo to afford a crude oil. Flash columnchromatography (silica gel, EtOAc, then 2% MeOH in EtOAc) gave 45 mg(54% for 2 steps) of acylsulfonamide 11 a. The method of this Example isalso shown in Scheme 8.

EXAMPLE 20

[0207] N-((Z)-7-{(1R,2R,3R,5S)-2-[(S)-(E)-5-(4-Chloro-5-methylthiophen-2-yl)-3-hydroxypent-1-enyl]-3,5-dihydroxycyclopentyl}hept-5-enoyl)methanesulfonamide(9b)

[0208] In accordance with the procedures described above for thesynthesis of 9a, the use of acid 5b gave 9b.

EXAMPLE 21

[0209] Ethanesulfonic Acid ((Z)-7-{(1R,2R,3R,5S)-2-[(S)-(E)-5-(4-chloro-5-methylthiophen-2-yl)-3-hydroxypent-1-enyl]-3,5-dihydroxycyclopentyl}hept-5-enoyl)amide(10b)

[0210] In accordance with the procedures described above for thesynthesis of 10a, the use of acid 5b (41 mg, 0.059 mmol) afforded 9 mg(29% for 2 steps) of 10b.

EXAMPLE 22

[0211] N-((Z)-7-{(1R, 2R, 3R,5S)-2-[(S)-(E)-5-(4-Chloro-5-methylthiophen-2-yl)-3-hydroxypent-1-enyl]-3,5-dihydroxycyclopentyl}hept-5-enoyl)-1,1,1-trifluoromethanesulfonamide(11 b)

[0212] In accordance with the procedures described above for thesynthesis of 11a, the use of acid 5b (41 mg, 0.059 mmol) gave thedesired product 11b along with an impurity. The impure product was thensuspended in CH₂Cl₂ and extracted with 1N NaOH. The organic phase wasdiscarded and the basic aqueous phase was acidified to pH 1 with 1N HCl.The aqueous phase was extracted with EtOAc (3×), then the combinedorganic extracts were dried (Na₂SO₄), filtered and concentrated in vacuoto afford 15 mg (44% for 2 steps) of 11b.

EXAMPLE 23

[0213]N-((Z)-7-{(1R,2R,3R,5S)-2-[((S)-(E)-5-(5-Chlorothiophen-2-yl)-3-hydroxypent-1-enyl)-3,5-dihydroxycyclopentyl]hept-5-enoyl}methanesulfonamide(9c)

[0214] The synthesis of 9c was carried out in accordance with theprocedures described above for the synthesis of 9a, with the followingexceptions: acid 5c (50 mg, 0.073 mmol) was used in place of acid 5a;intermediate 6c was purified by flash column chromatography (silica gel,45% EtOAc/Hex) to give 43 mg (77%); and a different hydrolysis method(step 2) was used, as described below.

[0215] Purified 6c (43 mg, 0.057 mmol) was dissolved in THF (0.1 mL),H₂O (0.1 mL) and acetic acid (0.4 mL). The mixture was heated at 35° C.under nitrogen for 42 h. The mixture was cooled and diluted with EtOAc,washed with water and brine, then dried (Na₂SO₄), filtered andconcentrated in vacuo. Purification by flash column chromatography(silica gel, EtOAc, then 2% MeOH in EtOAc) gave 9 mg (31%) of 9c.

EXAMPLE 24

[0216] Ethanesulfonic Acid((Z)-7-{(1R,2R,3R,5S)-2-[(S)-(E)-5-(5-chlorothiophen-2-yl)-3-hydroxypent-1-enyl]-3,5-dihydroxycyclopentyl}hept-5-enoyl)amide(10c)

[0217] In accordance with the procedures described above for thesynthesis of 10a, the use of acid 5c (100 mg, 0.15 mmol) gave 24 mg (31%for 2 steps) of 10c.

EXAMPLE 25

[0218] N-((Z)-7-{(1R, 2R, 3R,5S)-2-[(S)-(E)-5-(5-Chlorothiophen-2-yl)-3-hydroxypent-1-enyl]-3,5-dihydroxycyclopentyl}hept-5-enoyl)-1,1,1-trifluoromethanesulfonamide(11c)

[0219] In accordance with the procedures described above for thesynthesis of 11b, the use of acid 5c (100 mg, 0.15 mmol) gave 33 mg (40%for 2 steps) of 11c.

EXAMPLE 26

[0220]N-((Z)-7-{(1R,2R,3R,5S)-2-[((S)-(E)-5-(5-Iodothiophen-2-yl)-3-hydroxypent-1-enyl)-3,5-dihydroxycyclopentyl]hept-5-enoyl}methanesulfonamide(9d)

[0221] In accordance with the procedures described above for thesynthesis of 9a, the use of acid 5d (45 mg, 0.056 mmol) gave 15 mg (45%for 2 steps) of 9d.

EXAMPLE 27

[0222] Ethanesulfonic Acid((Z)-7-{(1R,2R,3R,5S)-2-[(S)-(E)-5-(5-iodothiophen-2-yl)-3-hydroxypent-1-enyl]-3,5-dihydroxycyclopentyl}hept-5-enoyl)amide(10d)

[0223] In accordance with the procedures described above for thesynthesis of 10a, the use of acid 5d (45 mg, 0.056 mmol) gave 10 mg (29%for 2 steps) of 10d.

EXAMPLE 28

[0224] N-((Z)-7-{(1R, 2R, 3R,5S)-2-[(S)-(E)-5-(5-Iodothiophen-2-yl)-3-hydroxypent-1-enyl]-3,5-dihydroxycyclopentyl}hept-5-enoyl)-1,1,1-trifluoromethanesulfonamide(11d)

[0225] In accordance with the procedures described above for thesynthesis of 11b, the use of acid 5d (45 mg, 0.056 mmol) gave 20 mg (55%for 2 steps) of 11d.

EXAMPLE 29

[0226]N-((Z)-7-{(1R,2R,3R,5S)-2-[((S)-(E)-5-(5-Bromothiophen-2-yl)-3-hydroxypent-1-enyl)-3,5-dihydroxycyclopentyl]hept-5-enoyl}methanesulfonamide(9e)

[0227] The syntheisis of 9e was carried out in accordance with theprocedures described above for the synthesis of 9a, with the followingexceptions: acid 5e (200 mg, 0.28 mmol) was used in place of acid 5a;intermediate 6e was purified by flash column chromatography (silica gel,45% EtOAc/hex) to afford 180 mg (81%) of 6e; deprotection of 6e (36 mg,0.045 mmol) afforded 13 mg (53%) of 9e.

EXAMPLE 30

[0228] Ethanesulfonic Acid ((Z)-7-{(1R,2R,3R,5S)-2-[(S)-(E)-5-(5-bromothiophen-2-yl)-3-hydroxypent-1-enyl]-3,5-dihydroxycyclopentyl}hept-5-enoyl)amide(10e)

[0229] In accordance with the procedures described above for thesynthesis of 10a, the use of acid 5e (45 mg, 0.062 mmol) gave 7 mg (20%for 2 steps) of 10e.

EXAMPLE 31

[0230] N-((Z)-7-{(1R, 2R, 3R,5S)-2-[(S)-(E)-5-(5-Bromothiophen-2-yl)-3-hydroxypent-1-enyl]-3,5-dihydroxycyclopentyl}hept-5-enoyl)-1,1,1-trifluoromethanesulfonamide(11e)

[0231] In accordance with the procedures described above for thesynthesis of 11b, the use of acid 5e (45 mg, 0.062 mmol) gave 22 mg (59%for 2 steps) of 11e.

EXAMPLE 32

[0232]N-((Z)-7-{(1R,2R,3R,5S)-3,5-Dihydroxy-2-[((S)-(E)-3-hydroxy-5-(2-methylthiophen-3-yl)pent-1-enyl)cyclopentyl}hept-5-enoyl)methanesulfonamide(9f)

[0233] In accordance with the procedures described above for thesynthesis of 9a, the use of acid 5f (200 mg, 0.30 mmol) gave 52 mg (37%for 2 steps) of 9f.

EXAMPLE 33

[0234] Ethanesulfonic Acid((Z)-7-{(1R,2R,3R,5S)-3,5-dihydroxy-2-[((S)-(E)-3-hydroxy-5-(2-methylthiophen-3-yl)pent-1-enyl]cyclopentyl}hept-5-enoyl)amide(10f)

[0235] In accordance with the procedures described above for thesynthesis of 10a, the use of acid 5f (200 mg, 0.30 mmol) afforded 110 mg(73% for 2 steps)of 10f.

EXAMPLE 34

[0236]N-((Z)-7-{(1R,2R,3R,5S)-3,5-Dihydroxy-2-[((S)-(E)-3-hydroxy-5-(2-methylthiophen-3-yl)pent-1-enyl]cyclopentyl}hept-5-enoyl)-1,1,1-trifluoromethanesulfonamide(11 f)

[0237] According to the procedures above for 11a, the use of acid 5f(111 mg, 0.17 mmol) gave 51 mg (56% for 2 steps) of 11f.

EXAMPLE 35

[0238]7-[(1R,2R,3R,5S)-2-[(S)-(E)-5-(2-Methylthiophen-3-yl)-3-(tetrahydropyran-2-yloxy)pent-1-enyl]-3,5-bis(tetrahydropyran-2-yloxy)cyclopentyl]heptanoicAcid (13)

[0239] Step 1: Preparation of the Partially Saturated Ester 12

[0240] Dienyl ester 4f (160 mg, 0.24 mmol) was dissolved in THF (1.0 mL)then tris(triphenylphosphine)rhodium(I) chloride (55 mg, 0.059 mmol) wasadded. The reaction was evacuated and purged under an atmosphere ofhydrogen. After sstirring for 24 h the reaction was concentrated invacuo. Purification of the crude residue by flash column chromatography(silica gel, 20% EtOAc/hex) afforded 151 mg (94%) of 12.

[0241] Step 2: Saponification of Ester 12

[0242] A solution of ester 12 (151 mg, 0.22 mmol) in THF (2.2 mL) wastreated with lithium hydroxide (0.9 mL of a 1.0N solution in H₂O, 0.9mmol). After 20 h stirring at room temperature, the reaction mixture wasconcentrated in vacuo, diluted with H₂O and acidified to pH 3 with 1NHCl. The aqueous mixture was extracted with EtOAc (2×), then thecombined extracts were dried (Na₂SO₄), filtered and concentrated invacuo. Purification of the crude residue by flash column chromatography(silica gel, 33% EtOAc/hex) afforded 130 mg (88%) of 13. The method ofthe Example is shown in Scheme 9.

EXAMPLE 36

[0243]N-(7-{(1R,2R,3R,5S)-3,5-Dihydroxy-2-[((S)-(E)-3-hydroxy-5-(2-methylthiophen-3-yl)pent-1-enyl)cyclopentyl}heptanoyl)methanesulfonamide(14)

[0244] In accordance with the procedures given above for the synthesisof 9a, the use of acid 13 (37 mg, 0.056 mmol) gave 13 mg (48% for 2steps) of 14. The method of the Example is also shown in Scheme 9.

EXAMPLE 37

[0245] Ethanesulfonic Acid(7-{(1R,2R,3R,5S)-3,5-dihydroxy-2-[((S)-(E)-3-hydroxy-5-(2-methylthiophen-3-yl)pent-1-enyl]cyclopentyl}heptanoyl)amide(15)

[0246] In accordance with the procedures given above for the synthesisof 10a, the use of acid 13 (37 mg, 0.056 mmol) gave 9 mg (32% for 2steps) of 15.

EXAMPLE 38

[0247]N-(7-{(1R,2R,3R,5S)-3,5-Dihydroxy-2-[((S)-(E)-3-hydroxy-5-(2-methylthiophen-3-yl)pent-1-enyl]cyclopentyl}heptanoyl)-1,1,1-trifluoromethanesulfonamide(16)

[0248] In accordance with the procedures given above for the synthesisof 11b, the use of acid 13 (37 mg, 0.056 mmol) gave 14 mg (46% for 2steps) of 16.

EXAMPLE 39

[0249] Acetic acid({(Z)-7-[(1R,2R,3R,5S)-3,5-dihydroxy-2-((S)-(E)-3-hydroxyoct-1-enyl)-cyclopentyl]hept-5-enoyl}methanesulfonylamino)methylEster (17g)

[0250] Step 1: Preparation of the THP-Protected Prodrug

[0251] Diisopropropylethylamine (0.23 mL, 1.32 mmol) and bromomethylacetate (0.11 mL, 1.12 mmol) were added sequentially to a solution of 6g(110 mg, 0.161 mmol) in DMF (1.0 mL) and the resulting solution wasstirred at room temperature under an atmosphere of nitrogen overnight.The solution was concentrated in vacuo. Purification of the cruderesidue by flash column chromatography (silica gel, 35% EtOAc/hex)afforded 109 mg (90%) of the THP protected prodrug.

[0252] Step 2: Deprotection of the THP-Protected Prodrug

[0253] A solution of the THP-protected prodrug (109 mg, 0.144 mmol) inMeOH (1.5 mL) was treated with PPTs (8 mg, 0.032 mmol). The solution washeated at 45° C. under an atmosphere of nitrogen. After 16 h, thereaction mixture was cooled then concentrated in vacuo to afford a crudeoil. Flash column chromatography (silica gel, EtOAc, then 2% MeOH inEtOAc) gave 47 mg (65%) of 17g. See FIG. 2.

EXAMPLE 40

[0254] 2,2-Dimethylpropionic acid ({(Z)-7-[(1R,2R,3R,5S)-3,5-dihydroxy-2-((S)-(E)-3-hydroxyoct-1-enyl)-cyclopentyl]hept-5-enoyl}methanesulfonylamino)methylEster (18g)

[0255] Step 1: Preparation of the THP-Protected Prodrug

[0256] Diisopropropylethylamine (0.25 mL, 1.44 mmol), sodium iodide (187mg, 1.25 mmol) and chloromethyl pivalate (0.18 mL, 1.25 mmol) were addedsequentially to a solution of 6g (121 mg, 0.177 mmol) in DMF (1.1 mL)and the resulting mixture was stirred at room temperature under anatmosphere of nitrogen overnight. The reaction mixture was diluted withEtOAc, washed with brine (3×), dried (Na₂SO₄), filtered and concentratedin vacuo. Purification of the crude residue by flash columnchromatography (silica gel, 25% EtOAc/hex) afforded 94 mg (67%) of theTHP protected prodrug.

[0257] Step 2: Deprotection of the THP-Protected Prodrug

[0258] A solution of the crude THP-protected acylsulfonamide derivative(93 mg, 0.117 mmol) in MeOH (1.2 mL) was treated with PPTs (7 mg, 0.028mmol). The solution was heated at 45° C. under an atmosphere ofnitrogen. After 24 h, the reaction mixture was cooled then concentratedin vacuo to afford a crude oil. Flash column chromatography (silica gel,100% EtOAc, then 2% MeOH in EtOAc) gave 47 mg (65%) of 18g. See FIG. 3.

EXAMPLE 41

[0259] Acetic Acid[((Z)-7-{(1R,2R,3R,5S)-2-[((S)-(E)-5-(5-bromo-4-methylthiophen-2-yl)-3-hydroxypent-1-enyl)-3,5-dihydroxycyclopentyl}hept-5-enoyl)methanesulfonyl-amino]Methyl Ester (17a)

[0260] In accordance with the procedures given above for the synthesisof 17g, the use of 6a (70 mg, 0.086 mmol) gave 21 mg (38% for 2 steps)of 17a. See FIG. 2.

EXAMPLE 42

[0261] 2,2-Dimethylpropionic acid [((Z)-7-{(1R,2R,3R,5S)-2-[((S)-(E)-5-(5-bromo-4-methylthiophen-2-yl)-3-hydroxypent-1-enyl)-3,5-dihydroxycyclopentyl}hept-5-enoyl)methanesulfonyl-amino]Methyl Ester (18a)

[0262] In accordance with the procedures given above for the synthesisof 18g, the use of 6a (78 mg, 0.95 mmol) gave 28 mg (43% for 2 steps) of18a. See FIG. 3.

EXAMPLE 43

[0263] Acetic Acid[((Z)-7-{(1R,2R,3R,5S)-2-[((S)-(E)-5-(4-chloro-5-methylthiophen-2-yl)-3-hydroxypent-1-enyl)-3,5-dihydroxycyclopentyl}hept-5-enoyl)methanesulfonyl-amino]Methyl Ester (17b)

[0264] In accordance with the procedures given above for the synthesisof 17g, the use of 6b (60 mg, 0.078 mmol) gave 28 mg (61% for 2 steps)of 17b. See FIG. 2.

EXAMPLE 44

[0265] 2,2-Dimethylpropionic Acid[((Z)-7-{(1R,2R,3R,5S)-2-[((S)-(E)-5-(4-chloro-5-methyl-thiophen-2-yl)-3-hydroxypent-1-enyl)-3,5-dihydroxycyclopentyl}hept-5-enoyl)methane-sulfonyl-amino]Methyl Ester (18b)

[0266] In accordance with the procedures given above for the synthesisof 18g, the use of 6b (60 mg, 0.078 mmol) gave 33 mg (67% for 2 steps)of 18b. See FIG. 3.

EXAMPLE 45

[0267] Acetic Acid[((Z)-7-{(1R,2R,3R,5S)-2-[((S)-(E)-5-(5-bromothiophen-2-yl)-3-hydroxypent-1-enyl)-3,5-dihydroxycyclopentyl}hept-5-enoyl)methanesulfonylamino]Methyl Ester (17e)

[0268] In accordance with the procedures given above for the synthesisof 17g, the use of 6e (72 mg, 0.090 mmol) gave 35 mg (63% for 2 steps)of 17e. See FIG. 2.

EXAMPLE 46

[0269] 2,2-Dimethylpropionic acid[((Z)-7-{(1R,2R,3R,5S)-2-[((S)-(E)-5-(5-bromothiophen-2-yl)-3-hydroxypent-1-enyl)-3,5-dihydroxycyclopentyl}hept-5-enoyl)methanesulfonyl-amino]Methyl Ester (18e)

[0270] In accordance with the procedures given above for the synthesisof 18g, the use of 6e (72 mg, 0.090 mmol) gave 38 mg (64% for 2 steps)of 18e. See FIG. 3.

EXAMPLE 47

[0271]N-{(Z)-7-[(1R,2R,3R,5S)-3,5-Dihydroxy-2-((S)-(E)-3-hydroxyoct-1-enyl)cyclopentyl]-hept-5-enoyl}benzenesulfonamide(19g)

[0272] Step 1: Preparation of the Tris-THP Benzenesulfonamide

[0273] Tris-THP PGF_(2α) (150 mg, 0.255 mmol), EDCI (69 mg, 0.36 mmol),DMAP (37 mg, 0.30 mmol) and benzenesulfonamide (120 mg, 0.763 mmol) weredissolved in DMF (1.2 mL) and the resulting solution was stirred at roomtemperature under an atmosphere of nitrogen. After 15 h the solution wasdiluted with EtOAc and washed with 1 N aqueous HCl (3×) and brine (1×),then dried (Na₂SO₄), filtered and concentrated in vacuo to afford acrude oil. Flash column chromatography (silica gel, 40% EtOAc/Hex) gave150 mg (79%) of tris-THP PGF_(2α) benzenesulfonamide.

[0274] Step 2: Deprotection of the Tris-THP Benzenesulfonamide

[0275] A solution of tris-THP PGF_(2α) benzenesulfonamide (150 mg, 0.201mmol) in MeOH (2.0 mL) was treated with PPTs (10 mg, 0.040 mmol). Thesolution was heated at 45° C. under an atmosphere of nitrogen. After 16h, the reaction mixture was cooled then concentrated in vacuo to afforda crude oil. Flash column chromatography (silica gel, EtOAc, then 2%MeOH in EtOAc) gave 48 mg (48% for 2 steps) of 19g. See FIG. 4.

EXAMPLE 48

[0276]N-((Z)-7-{(1R,2R,3R,5S)-2-[((S)-(E)-5-(4-Chloro-5-methylthiophen-2-yl)-3-hydroxypent-1-enyl)-3,5-dihydroxycyclopentyl]hept-5-enoyl}benzenesulfonamide(19b)

[0277] In accordance with the procedures given above for the synthesisof 19g, the use of 5b (125 mg, 0.175 mmol) gave 50 mg (49% for 2 steps)of 19b. See FIG. 4.

[0278] The effects of the compounds of this invention on intraocularpressure are also provided in the following tables. The compounds wereprepared at the said concentrations in a vehicle comprising 0.1%polysorbate 80 and 10 mM TRIS base. Dogs were treated by administering25 μl to the ocular surface, the contralateral eye received vehicle as acontrol. Intraocular pressure was measured by applanationpneumatonometry. Dog intraocular pressure was measured immediatelybefore drug administration and at 6 hours thereafter.

[0279] Compounds 9a, 9b, 9c, 9e, 10a, 18a, and 19b were examined andshowed a pronounced ocular hypotensive effect in dogs. Compound # IOPmax % decrease time (Hr) IOP max mmHg time (Hr)  9a −13.6% (72 hr):0.03% −2.8 (72 hr): 0.03%  9b −26.5 (96 hr): 0.03% −4.9 (96 hr): 0.03% 9c −23.8% (102 hr): 0.03% −4.2 (102 hr): 0.03%  9e −11.7% (100 hr):0.03% −2.0 (100 hr): 0.03% 10a −24.9% (4 hr): 0.03% −5.1 (4 hr): 0.03%18a −22.0 (24 hr): 0.03% −3.9 (24 hr): 0.03% 19b −13.0% (74 hr): 0.03%−2.6 (74 hr): 0.03%

[0280] The foregoing description details specific methods andcompositions that can be employed to practice the present invention, andrepresents the best mode contemplated. However, it is apparent for oneof ordinary skill in the art that further compounds with the desiredpharmacological properties can be prepared in an analogous manner, andthat the disclosed compounds can also be obtained from differentstarting compounds via different chemical reactions. Similarly,different pharmaceutical compositions may be prepared and used withsubstantially the same result. Thus, however detailed the foregoing mayappear in text, it should not be construed as limiting the overall scopehereof, rather, the ambit of the present invention is to be governedonly by the lawful construction of the appended claims.

1. A novel compound represented by the general formula I;

wherein a hatched line represents the α configuration, a trianglerepresents the β configuration, a straight line, e.g. at the 9, 11 or 15position represents either the α or β configuration, a dotted linerepresents the presence or absence of a double bond; a wavy linerepresents a cis or trans bond; X is O, S, NH or (CH₂)_(n); n is 0 or aninteger of from 1 to 4; Y is C₁-C₅ n-alkyl, C₃-C₇ cycloalkyl, phenyl,furanyl, thienyl, pyridinyl, thiazolyl, benzothienyl, benzofuranyl,naphthyl, or substituted derivatives thereof, wherein the substituentsmaybe selected from the group consisting of C₁-C₅ alkyl, halogen, CF₃,CN, NO₂, N(R²)₂, CO₂R² and OR²; Z is (CH₂)_(n) or a covalent bond; R isC₁-C₆ lower alkyl, benzyl or Z-CF₃ or mesylate or triflate; R¹ is H, R²or COR²; provided however, said compound is notN-{(Z)-7-[(1R,2R,3R,5S)-3,5-Dihydroxy-2-((S)-(E)-3-hydroxyoct-1-enyl)cyclopentyl]-hept-5-enoyl}methanesulfonamide,N-{(Z)-7-[(1R,2R,3R,5S)-3,5-Dihydroxy-2-((S)-(E)-3-hydroxy-5-phenylpent-1-enyl)cyclopentyl]-hept-5-enoyl}methanesulfonamide,orN-{(Z)-7-[(1R,2R,3R,5S)-3,5-Dihydroxy-2-((S)-(E)-3-hydroxyoct-1-enyl)cyclopentyl]-hept-5-enoyl}benzenesulfonamide.2. The compound according to claim 1 wherein said compound isrepresented by the general formula II;


3. The compound according to claim 2 wherein said compound isrepresented by the general formula III;


4. The compound of claim 2 wherein X is CH_(2.)
 5. The compound of claim2 wherein Y is selected from the group consisting of n-propyl, thienyland halo or lower C₁ to C₄ alkyl substituted derivatives of thienyl. 6.The compound of claim 2 wherein Z is a covalent bond.
 7. The compound ofclaim 6 wherein R is selected from the group consisting methyl, ethyl,n-propyl, n-butyl, CF₃, mesylate and triflate.
 8. The compound of claim6 wherein R¹ is H, methyl, ethyl, acetyl and pivaloyl.
 9. The compoundof claim 6 wherein R² is H.
 10. The compound of claim 1 wherein saidcompound is selected from the group consisting of; Ethanesulfonic acid{(Z)-7-[(1R,2R,3R,5S)-3,5-dihydroxy-2-((S)-(E)-3-hydroxyoct-1-enyl)cyclopentyl]hept-5-enoyl}amideEthanesulfonic acid{(Z)-7-[(1R,2R,3R,5S)-3,5-dihydroxy-2-((R)-(E)-3-hydroxyoct-1-enyl)cyclopentyl]hept-5-enoyl}amidePropane-1-sulfonic acid {(Z)-7-[(1R,2R,3R,5S)-3,5-dihydroxy-2-((S)-(E)-3-hydroxyoct-1-enyl)cyclopentyl]hept-5-enoyl}amidePropane-1-sulfonic acid{(Z)-7-[(1R,2R,3R,5S)-3,5-dihydroxy-2-((R)-(E)-3-hydroxyoct-1-enyl)cyclopentyl]hept-5-enoyl}amideButane-1-sulfonic acid{(Z)-7-[(1R,2R,3R,5S)-3,5-dihydroxy-2-((S)-(E)-3-hydroxyoct-1-enyl)cyclopentyl]hept-5-enoyl}amideButane-1-sulfonic acid{(Z)-7-[(1R,2R,3R,5S)-3,5-dihydroxy-2-((R)-(E)-3-hydroxyoct-1-enyl)cyclopentyl]hept-5-enoyl}amideN-{(Z)-7-[(1R,2R,3R,5S)-3,5-Dihydroxy-2-((S)-(E)-3-hydroxyoct-1-enyl)cyclopentyl]-hept-5-enoyl}N-methylmethanesulfonamideN-{(Z)-7-[(1R,2R,3R,5S)-3,5-Dihydroxy-2-((S)-(E)-3-hydroxyoct-1-enyl)cyclopentyl]-hept-5-enoyl}N-ethylmethanesulfonamide2,2-Dimethylpropionic acid(1R,2R,3R,5S)-4-hydroxy-2-((S)-(E)-3-hydroxyoct-1-enyl)-3-((Z)-7-methanesulfonylamino-7-oxohept-2-enyl)cyclopentylester N-{(Z)-7-[(1R,2R,3R,5S)-3,5-Dihydroxy-2-((S)-(E)-3-hydroxyoct-1-enyl)cyclopentyl]-hept-5-enoyl}-1,1,1-trifluoromethanesulfonamideN-{(E)-7-[(1R,2R,3R,5S)-3,5-Dihydroxy-2-((S)-(E)-3-hydroxy-5-phenylpent-1-enyl)-cyclopentyl]hept-5-enoyl}methanesulfonamideEthanesulfonic acid((Z)-7-{(1R,2R,3R,5S)-2-[(S)-(E)-5-(4-bromo-5-methylthiophen-2-yl)-3-hydroxypent-1-enyl]-3,5-dihydroxycyclopentyl}hept-5-enoyl)amideN-((Z)-7-{(1R,2R,3R,5S)-2-((S)-(E)-5-(5-Bromo-4-methylthiophen-2-yl)-3-hydroxypent-1-enyl)-3,5-dihydroxycyclopentyl]hept-5-enoyl}methanesulfonamideEthanesulfonic acid((Z)-7-{(1R,2R,3R,5S)-2-((S)-(E)-5-(5-bromo-4-methylthiophen-2-yl)-3-hydroxypent-1-enyl)-3,5-dihydroxycyclopentyl]hept-5-enoyl}amideN-((Z)-7-{(1R,2R,3R,5S)-2-[((S)-(E)-5-(5-Bromo-4-methylthiophen-2-yl)-3-hydroxypent-1-enyl)-3,5-dihydroxycyclopentyl]hept-5-enoyl}-1,1,1-trifluoromethanesulfonamideN-((Z)-7-{(1R,2R,3R,5S)-2-[((S)-(E)-5-(4-Chloro-5-methylthiophen-2-yl)-3-hydroxypent-1-enyl)-3,5-dihydroxycyclopentyl]hept-5-enoyl}methanesulfonamideEthanesulfonic acid((Z)-7-{(1R,2R,3R,5S)-2-[((S)-(E)-5-(4-chloro-5-methylthiophen-2-yl)-3-hydroxypent-1-enyl)-3,5-dihydroxycyclopentyl]hept-5-enoyl}amideN-((Z)-7-{(1R,2R,3R,5S)-2-[((S)-(E)-5-(4-Chloro-5-methylthiophen-2-yl)-3-hydroxypent-1-enyl)-3,5-dihydroxycyclopentyl]hept-5-enoyl}-1,1,1-trifluoromethanesulfonamideN-((Z)-7-{(1R,2R,3R,5S)-3,5-Dihydroxy-2-[((S)-(E)-3-hydroxy-5-(2-methylthiophen-3-yl)pent-1-enyl)cyclopentyl}hept-5-enoyl)methanesulfonamideEthanesulfonic acid((Z)-7-{(1R,2R,3R,5S)-3,5-dihydroxy-2-[((S)-(E)-3-hydroxy-5-(2-methylthiophen-3-yl)pent-1-enyl]cyclopentyl}hept-5-enoyl)amideN-((Z)-7-{(1R,2R,3R,5S)-3,5-Dihydroxy-2-[((S)-(E)-3-hydroxy-5-(2-methylthiophen-3-yl)pent-1-enyl]cyclopentyl}hept-5-enoyl)-1,1,1-trifluoromethanesulfonamideN-((Z)-7-{(1R,2R,3R,5S)-3,5-Dihydroxy-2-[((S)-(E)-3-hydroxy-5-(2-methylthiophen-3-yl)pent-1-enyl)cyclopentyl}heptanoyl)methanesulfonamideEthanesulfonic acid((Z)-7-{(1R,2R,3R,5S)-3,5-dihydroxy-2-[((S)-(E)-3-hydroxy-5-(2-methylthiophen-3-yl)pent-1-enyl]cyclopentyl}heptanoyl)amideN-((Z)-7-{(1R,2R,3R,5S)-3,5-Dihydroxy-2-[((S)-(E)-3-hydroxy-5-(2-methylthiophen-3-yl)pent-1-enyl]cyclopentyl}heptanoyl)-1,1,1-trifluoromethanesulfonamideN-((Z)-7-{(1R,2R,3R,5S)-2-[((S)-(E)-5-(5-Chlorothiophen-2-yl)-3-hydroxypent-1-enyl)-3,5-dihydroxycyclopentyl]hept-5-enoyl}methanesulfonamideEthanesulfonic acid ((Z)-7-{(1R,2R,3R,5S)-2-[((S)-(E)-5-(5-chlorothiophen-2-yl)-3-hydroxypent-1-enyl)-3,5-dihydroxycyclopentyl]hept-5-enoyl}amideN-((Z)-7-{(1R,2R,3R,5S)-2-[((S)-(E)-5-(5-Chlorothiophen-2-yl)-3-hydroxypent-1-enyl)-3,5-dihydroxycyclopentyl]hept-5-enoyl}-1,1,1-trifluoromethanesulfonamideN-((Z)-7-{(1R,2R,3R,5S)-3,5-Dihydroxy-2-[((S)-(E)-3-hydroxy-5-(5-iodothiophen-2-yl)pent-1-enyl)cyclopentyl}heptanoyl)methanesulfonamideEthanesulfonic acid((Z)-7-{(1R,2R,3R,5S)-3,5-dihydroxy-2-[((S)-(E)-3-hydroxy-5-(5-iodothiophen-2-yl)pent-1-enyl]cyclopentyl}heptanoyl)amideN-((Z)-7-{(1R,2R,3R,5S)-3,5-Dihydroxy-2-[((S)-(E)-3-hydroxy-5-(5-iodothiophen-2-yl)pent-1-enyl]cyclopentyl}heptanoyl)-1,1,1-trifluoromethanesulfonamideN-((Z)-7-{(1R,2R,3R,5S)-2-[((S)-(E)-5-(5-Bromothiophen-2-yl)-3-hydroxypent-1-enyl)-3,5-dihydroxycyclopentyl]hept-5-enoyl}methanesulfonamideEthanesulfonic acid((Z)-7-{(1R,2R,3R,5S)-2-[((S)-(E)-5-(5-bromothiophen-2-yl)-3-hydroxypent-1-enyl)-3,5-dihydroxycyclopentyl]hept-5-enoyl}amideN-((Z)-7-{(1R,2R,3R,5S)-2-[((S)-(E)-5-(5-Bromothiophen-2-yl)-3-hydroxypent-1-enyl)-3,5-dihydroxycyclopentyl]hept-5-enoyl}-1,1,1-trifluoromethanesulfonamideAcetic acid({(Z)-7-[(1R,2R,3R,5S)-3,5-dihydroxy-2-((S)-(E)-3-hydroxyoct-1-enyl)-cyclopentyl]hept-5-enoyl}methanesulfonylamino)methylester 2,2-Dimethylpropionic acid({(Z)-7-[(1R,2R,3R,5S)-3,5-dihydroxy-2-((S)-(E)-3-hydroxyoct-1-enyl)-cyclopentyl]hept-5-enoyl}methanesulfonylamino)methylester Acetic acid[((Z)-7-{(1R,2R,3R,5S)-2-[((S)-(E)-5-(5-bromo-4-methylthiophen-2-yl)-3-hydroxypent-1-enyl)-3,5-dihydroxycyclopentyl}hept-5-enoyl)methanesulfonyl-amino]methyl ester 2,2-Dimethylpropionic acid[((Z)-7-{(1R,2R,3R,5S)-2-[((S)-(E)-5-(5-bromo-4-methylthiophen-2-yl)-3-hydroxypent-1-enyl)-3,5-dihydroxycyclopentyl}hept-5-enoyl)methanesulfonyl-amino]methyl ester Acetic acid[((Z)-7-{(1R,2R,3R,5S)-2-[((S)-(E)-5-(4-chloro-5-methylthiophen-2-yl)-3-hydroxypent-1-enyl)-3,5-dihydroxycyclopentyl}hept-5-enoyl)methanesulfonyl-amino]methyl ester 2,2-Dimethylpropionic acid[((Z)-7-{(1R,2R,3R,5S)-2-[((S)-(E)-5-(4-chloro-5-methyl-thiophen-2-yl)-3-hydroxypent-1-enyl)-3,5-dihydroxycyclopentyl}hept-5-enoyl)methane-sulfonyl-amino]methyl ester Acetic acid [((Z)-7-{(1R,2R,3R,5S)-2-[((S)-(E)-5-(5-bromothiophen-2-yl)-3-hydroxypent-1-enyl)-3,5-dihydroxycyclopentyl}hept-5-enoyl)methanesulfonylamino]methyl ester and 2,2-Dimethylpropionic acid[((Z)-7-{(1R,2R,3R,5S)-2-[((S)-(E)-5-(5-bromothiophen-2-yl)-3-hydroxypent-1-enyl)-3,5-dihydroxycyclopentyl}hept-5-enoyl)methanesulfonyl-amino]methyl ester andN-((Z)-7-{(1R,2R,3R,5S)-2-[((S)-(E)-5-(4-Chloro-5-methylthiophen-2-yl)-3-hydroxypent-1-enyl)-3,5-dihydroxycyclopentyl]hept-5-enoyl}benzenesulfonamide11. The novel compound of claim 10 wherein said compound is selectedfrom the group consisting of; N-((Z)-7-{(1R,2R,3R,5S)-2-[(S)-(E)-5-(5-Bromo-4-methylthiophen-2-yl)-3-hydroxypent-1-enyl]-3,5-dihydroxycyclopentyl}hept-5-enoyl)methanesulfonamideN-((Z)-7-{(1R,2R,3R,5S)-2-[(S)-(E)-5-(4-Chloro-5-methylthiophen-2-yl)-3-hydroxypent-1-enyl]-3,5-dihydroxycyclopentyl}hept-5-enoyl)methanesulfonamideN-((Z)-7-{(1R,2R,3R,5S)-2-[((S)-(E)-5-(5-Chlorothiophen-2-yl)-3-hydroxypent-1-enyl)-3,5-dihydroxycyclopentyl]hept-5-enoyl}methanesulfonamideN-((Z)-7-{(1R,2R,3R,5S)-2-[((S)-(E)-5-(5-Bromothiophen-2-yl)-3-hydroxypent-1-enyl)-3,5-dihydroxycyclopentyl]hept-5-enoyl}methanesulfonamideEthanesulfonic acid ((Z)-7-{(1R,2R,3R,5S)-2-[(S)-(E)-5-(5-bromo-4-methylthiophen-2-yl)-3-hydroxypent-1-enyl]-3,5-dihydroxycyclopentyl}hept-5-enoyl)amide2,2-Dimethylpropionic acid[((Z)-7-{(1R,2R,3R,5S)-2-[((S)-(E)-5-(5-bromo-4-methylthiophen-2-yl)-3-hydroxypent-1-enyl)-3,5-dihydroxycyclopentyl}hept-5-enoyl)methanesulfonyl-amino]methyl ester andN-((Z)-7-{(1R,2R,3R,5S)-2-[((S)-(E)-5-(4-Chloro-5-methylthiophen-2-yl)-3-hydroxypent-1-enyl)-3,5-dihydroxycyclopentyl]hept-5-enoyl}benzenesulfonamide12. The novel compound of claim 1 wherein Y is thienyl substituted withat least one of chloro or bromo.